Association of Dishevelled with the Clathrin AP-2 Adaptor Is Required for Frizzled Endocytosis and Planar Cell Polarity Signaling

Yu, Ai‐Nong; Rual, Jean François; Tamai, Keiko; Harada, Yasuhiro; Vidal, Marc; He, Xi; Kirchhausen, Tomas

doi:10.1016/j.devcel.2006.10.015

Cited by 161 publications

(175 citation statements)

References 71 publications

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“…Dsh interacts with the clathrin AP-2 adaptor in part via its DEP domain and promotes endocytosis and degradation of Fz4 (27). Moreover, Wnt5a induces the formation of a complex between Dsh and the E3 ubiquitin ligases Smurf1 and Smurf2, promoting ubiquitination and degradation of Prickle, a cytoplasmic component of the non-canonical Wnt signaling pathway (36).…”

Section: Discussionmentioning

confidence: 99%

“…Role of Dishevelled in Syndecan4 Steady-state Levels-Because Dsh interacts with SDC4 (16) and binds to components of the endocytic pathway (27,28), we decided to evaluate the role of Dsh in regulating SDC4 steady-state levels. In gain-of-function experiments we found that Dsh reduces SDC4 steady-state levels (Fig.…”

Section: Non-canonical Wnt Signaling Reduces Cell Surface Levels and mentioning

confidence: 99%

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Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan4

Carvallo¹,

Muñoz²,

Bustos

et al. 2010

Journal of Biological Chemistry

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Dynamic regulation of cell adhesion receptors is required for proper cell migration in embryogenesis, tissue repair, and cancer. Integrins and Syndecan4 (SDC4) are the main cell adhesion receptors involved in focal adhesion formation and are required for cell migration. SDC4 interacts biochemically and functionally with components of the Wnt pathway such as Frizzled7 and Dishevelled. Non-canonical Wnt signaling, particularly components of the planar cell polarity branch, controls cell adhesion and migration in embryogenesis and metastasic events. Here, we evaluate the effect of this pathway on SDC4. We have found that Wnt5a reduces cell surface levels and promotes ubiquitination and degradation of SDC4 in cell lines and dorsal mesodermal cells from Xenopus gastrulae. Gain-and loss-of-function experiments demonstrate that Dsh plays a key role in regulating SDC4 steady-state levels. Moreover, a SDC4 deletion construct that interacts inefficiently with Dsh is resistant to Wnt5a-induced degradation. Non-canonical Wnt signaling promotes monoubiquitination of the variable region of SDC4 cytoplasmic domain. Mutation of these specific residues abrogates ubiquitination and results in increased SDC4 steadystate levels. This is the first example of a cell surface protein ubiquitinated and degraded in a Wnt/Dsh-dependent manner.Cell adhesion and migration are key processes for embryogenesis, inflammatory response, tissue repair, and cancer. Cell migration is a very dynamic process that requires the continuous assembly and disassembly of the cell surface complexes mediating cell-cell and cell-extracellular matrix adhesion (1, 2). Integrins and Syndecans are the main cell adhesion receptors involved in focal adhesion (FA) 5 formation and cell-extracellular matrix communication (3). FA formation of cells plated on fibronectin requires the specific engagement and synergism between ␣5␤1 integrin and Syndecan4 (SDC4)(3, 4).SDC4 is a cell surface heparan sulfate proteoglycan that activates intracellular signaling cascades through activation of PKC␣ (4). SDC4 overexpression or knockout compromises cell migration in normal (5) and tumorigenic cells (6). More recently it was demonstrated that SDC4 is required for localization of Rac1 and membrane protrusion formation at the leading edge to allow celldirected migration (7). In normal and tumorigenic cells, endocytosis and recycling of integrins modulate FA turnover and proper cell migration (8, 9). Which extracellular cues regulate the stability and turnover of FA receptors, in particular of SDC4, is a key question to understand cell migration.Wnt proteins constitute a large family of secreted glycoproteins that can activate diverse intracellular signaling pathways in a context-dependent manner. Wnt5a is known to promote polarized cell migration by activating a non-canonical Wnt pathway through the tyrosine kinase Ror2 receptor and c-Jun N-terminal kinase (10 -12). Wnt5a increases cell migration and invasiveness of tumorigenic cells by activation of FA kinase, PKC, Rac1, and promoti...

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Section: Discussionmentioning

confidence: 99%

Section: Non-canonical Wnt Signaling Reduces Cell Surface Levels and mentioning

confidence: 99%

Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan4

Carvallo¹,

Muñoz²,

Bustos

et al. 2010

Journal of Biological Chemistry

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“…In cells that have induced and high levels of Dab2, such as RA-differentiated F9 cells, the Wnt signalosome is either not properly endocytosed and/or not properly assembled at the plasma membrane due to AP-2 sequestration. Interestingly, AP-2 and Dvl associations have recently be shown to be required for frizzled endocytosis (Yu et al, 2007). We have previously demonstrated that Dab2 can interact with Dvl and that Dab2 overexpression can disrupt Axin/ Dvl interactions (Hocevar et al, 2003).…”

Section: Dab2 and Wnt Signaling Y Jiang Et Almentioning

confidence: 97%

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

2007

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b-Catenin-mediated Wnt signaling is essential in embryonic development and in adult tissues. Recent studies have demonstrated that Axin not only plays an important inhibitory role in coordinating b-catenin degradation, but is itself degraded by the low-density-lipoprotein receptorrelated protein (LRP)5/6 Wnt co-receptor. Here, we demonstrate that the endocytic adaptor molecule Disabled-2 (Dab2), which we have previously demonstrated to act as an inhibitor of b-catenin signaling, interacts with Axin and prevents its interaction with and degradation by the LRP5 co-receptor, thereby increasing its half-life and stabilization. Dab2 levels induced during retinoic acidinduced differentiation of F9, or during transforming growth factor-b-induced epithelial-mesenchymal transdifferentiation of mouse mammary epithelial cells result in the stabilization of Axin and concomitant inhibition of b-catenin signaling. Ectopic expression of Dab2 in F9 cells as well as in transformed cell lines results in increased Axin expression and attenuation of Wnt-mediated signaling. We conclude that Dab2 may play an important role in the maintenance of the differentiated state and restrain Wnt-mediated proliferation through its association with and modulation of Axin.

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“…Direct binding of a polybasic stretch in the DEP domain to negatively charged lipids was recently shown to contribute to formation of the Fz-Dvl complex at the PM (30). In addition, the Dvl2 DEP domain, aided by a YHEL motif in the Dvl C terminus, interacts with μ2-adaptin, a subunit of the AP-2 clathrin adaptor complex, to facilitate clathrin-mediated endocytosis of Fz4 and Dvl2 on Wnt activation (31,32). Both of these activities of the DEP domain are mainly linked to PCP signaling, however, leaving the role of the DEP domain in β-catenin-dependent signaling unexplained (29,(33)(34)(35)(36).…”

mentioning

confidence: 99%

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Tauriello

Jordens

Kirchner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

218

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Wnt binding to members of the seven-span transmembrane Frizzled (Fz) receptor family controls essential cell fate decisions and tissue polarity during development and in adulthood. The Fzmediated membrane recruitment of the cytoplasmic effector Dishevelled (Dvl) is a critical step in Wnt/β-catenin signaling initiation, but how Fz and Dvl act together to drive downstream signaling events remains largely undefined. Here, we use an Fz peptide-based microarray to uncover a mechanistically important role of the bipartite Dvl DEP domain and C terminal region (DEP-C) in binding a three-segmented discontinuous motif in Fz. We show that cooperative use of two conserved motifs in the third intracellular loop and the classic C-terminal motif of Fz is required for DEP-C binding and Wnt-induced β-catenin activation in cultured cells and Xenopus embryos. Within the complex, the Dvl DEP domain mainly binds the Fz C-terminal tail, whereas a short region at the Dvl C-terminal end is required to bind the Fz third loop and stabilize the Fz-Dvl interaction. We conclude that Dvl DEP-C binding to Fz is a key event in Wnt-mediated signaling relay to β-catenin. The discontinuous nature of the Fz-Dvl interface may allow for precise regulation of the interaction in the control of Wnt-dependent cellular responses.peptide microarray | protein-protein interaction | Wingless signaling

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Association of Dishevelled with the Clathrin AP-2 Adaptor Is Required for Frizzled Endocytosis and Planar Cell Polarity Signaling

Cited by 161 publications

References 71 publications

Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan4

Non-canonical Wnt Signaling Induces Ubiquitination and Degradation of Syndecan4

The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

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